Chemo-Immunotherapy: A New Trend in Cancer Treatment
Abstract
:Simple Summary
Abstract
1. Chemotherapy and Immunotherapy: Friends or Foes?
2. Immune Checkpoints
3. The Rationale behind the Combination of Chemotherapy with Immune Checkpoint Inhibitors
4. Chemotherapy May Boost Antitumor Immunity
4.1. Chemotherapy Activates T Cell Response
4.2. Chemotherapy Dampens the Immunosuppressive Tumor Microenvironment
4.3. Chemotherapy Activates NK Cells
5. Determinants of the Success of Chemo-Immunotherapy
5.1. The Right Dose of Chemotherapy
5.2. The Timing of Chemo-Immunotherapy
5.3. The Sequence of Chemo-Immunotherapy
6. Overview of Clinically Approved Chemo-Immunotherapy Combinations
Cancer | Line of Therapy | PD-L1 Positivity Criteria | Chemotherapy | ICI | Clinical Benefit | Trial Name |
---|---|---|---|---|---|---|
NSCLC-non-squamous | Metastatic, first-line | Regardless of PD-L1 tumor expression | Pemetrexed + carboplatin | Pembrolizumab | OS at 12 m: 69.2% vs. 49.4%. HR 0.49; [95% CI 0.38–0.64]; p < 0.00001 | Keynote-189 [4] |
NSCLC-squamous | Metastatic, first-line | Regardless of PD-L1 tumor expression | Carboplatin + paclitaxel/ nab paclitaxel | Pembrolizumab | OS: 15.9 vs. 11.3 m. HR 0.64; [95% CI 0.49–0.85]; p = 0.001 | Keynote-407 [68] |
NSCLC-non-squamous | Metastatic, first-line | Regardless of PD-L1 tumor expression | Carboplatin + paclitaxel + bevacizumab | Atezolizumab | OS: 19.2 vs. 14.7 m. HR 0.78; [95% CI 0.64–0.96]; p = 0.01 | IMpower 150 [69] |
NSCLC-non-squamous | Metastatic, first-line | Regardless of PD-L1 tumor expression | Carboplatin + nab paclitaxel | Atezolizumab | OS: 18.6 vs. 13.9 m. HR 0.8; [95% CI 0.64–0.99]; p = 0.03 | IMpower 130 [5] |
NSCLC | Metastatic, first-line | Regardless of PD-L1 tumor expression | Platinum doublet | Nivolumab + ipilimumab | OS 15.6 vs. 10.9 m; HR 0.69; [95% CI 0.55–0.80]; p = 0.00065 | CheckMate-9LA [70] |
NSCLC | Neoadjuvant | Regardless of PD-L1 tumor expression | Platinum-based chemotherapy | Nivolumab | EFS 31.6 vs. 20.8 m. HR 0.63; [97.3% CI, 0.43–0.91]; p = 0.005. pCR 24.0% vs. 2.2%. OR: 13.9; [99% CI, 3.4–55.7]; p < 0.001 | Checkmate-816 [71] |
NSCLC | Metastatic | PD-L1 expression on ≥1% of tumor cells | Platinum-based chemotherapy + tremelimumab | Durvalumab | Reduced the risk of death by 23% HR 0.77; [95% CI 0.65 to 0.92]; p = 0.00304 | POSEIDON Phase III trial [83] |
NSCLC | Metastatic, first-line | Regardless of PD-L1 tumor expression | Adjuvant treatment following surgical resection and platinum-based chemotherapy | Pembrolizumab | Reduced the risk of disease recurrence or death by 27%; HR 0.73; [95% CI, 0.60 to 0.89] | KEYNOTE-091 [84] |
SCLC | Extensive stage, first-line | Regardless of PD-L1 tumor expression | Carboplatin + etoposide | Atezolizumab concurrent and maintenance | OS: 12.3 vs. 10.3 m. HR 0.70; [95% CI 0.54–0.91]; p = 0.006 | IMpower 133 [73] |
SCLC | Extensive stage, first-line | Regardless of PD-L1 tumor expression | Carboplatin + etoposide | Durvalumab | OS: 13 vs. 10.3 m. HR 0.73; [95% CI 0.59–0.91]; p = 0.0047 | CASPIAN [62] |
HNSCC | Metastatic first-line | Regardless of PD-L1 tumor expression | Platinum + 5-FU or platinum + 5-FU + cetuximab | Pembrolizumab | OS: 13.6 vs. 10.4 m. (CPS ≥ 1) HR 0.65; [95% CI 0.53–0.80]; p < 0.03 | Keynote-048 [77] |
Esophagus cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | 5-fluorouracil + cisplatin | Pembrolizumab | OS: 12.4 vs. 9.8 m. HR 0.73; [CI 0.62–0.86]; p < 0.0001 | Keynote-590 [78] |
Esophagus cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | Fluropyrimidine + platinum-based | Nivolumab | OS: 13.2 vs. 10.7 m. HR 0.74; [99.1% CI, 0.58–0.96]; p = 0.002 | Checkmate 648 [79] |
Gastric/ esophagus cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | Capecitabine + oxaliplatin or leucovorin + fluorouracil + oxaliplatin | Nivolumab | OS: 13.1 vs. 11.1 m. HR 0.71; [98.4% CI 0.59–0.86]; p < 0.0001 | Check-Mate-649 [16] |
Gastric cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | Trastuzumab + 5-fluorouracil + cisplatin or capecitabine + oxaliplatin | Pembrolizumab | 22.7% improvement in OR [95% CI 11.2–33.7]; p = 0.00006. CR 11.3% vs. 3.1% | Keynote-811 [17] |
TNBC | Metastatic, first-line | PD-L1 + tumor cells (CPS ≥ 10) | Nab paclitaxel or paclitaxel or carboplatin + Gemcitabine | Pembrolizumab | PFS (CPS > 10): 9.7 vs. 5.6 m. HR 0.65; [95% CI 0.49–0.86]; p = 0.0012 | Keynote 355 [74] |
TNBC | Neoadjuvant | Regardless of PD-L1 tumor expression | Carboplatin + paclitaxel, followed by doxorubicin or epirubicin + cyclophosphamide | Pembrolizumab | 37% reduction in the risk of disease progression. HR = 0.63; [95% CI, 0.48–0.82]; p = 0.0003 | Keynote-522 [75] |
TNBC | Metastatic, first-line | PD-L1 + tumor cells (≥1%). | Nab paclitaxel | Atezolizumab | OS: 25.0 vs. 15.5 m. PD-L1(+) HR 0.62; [95% CI 0.45–0.86] | IMpassion 130 [76] |
Cervical cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | Paclitaxel + cisplatin or paclitaxel + carboplatin +/− bevacizumab | Pembrolizumab | ORR 68% vs. 50%. Median of duration response 18.0 vs. 10.4 m | Keynote-826 [82] |
Biliary tract cancer | Metastatic, first-line | Regardless of PD-L1 tumor expression | Gemcitabine + cisplatin | Durvalumab | Reduced the risk of death by 20% HR 0.80; [95% CI 0.66–0.97]; p = 0.021 | TOPAZ-1 [81] |
Bladder cancer | Metastatic, first-line maintenance | Regardless of PD-L1 tumor expression | Gemcitabine + cisplatin/carboplatin | Avelumab | OS 21.4 vs. 14.3 m; HR 0.69; [95% CI 0.56 to 0.86]; p = 0.001 | JAVELIN Bladder 100 [80] |
7. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
Glossary
Progression-free survival (PFS) | The time from treatment initiation until disease progression or worsening. It may be used as a direct or surrogate measure of clinical benefit for drug approvals. |
Pathological complete response (pCR) | Defined as no residual disease after treatment determined by the pathologist. |
Partial response (PR) | The decrease in the size of a tumor, or the extent of cancer in the body, in response to treatment. |
Overall survival (OS) | The time from treatment to death, with no restriction on the cause of death. It is universally accepted as a direct measure of clinical benefit; however, in some disease areas, surrogate end-points are used to try to reduce the time taken to analyze new treatments. |
Overall response rate (ORR) | The proportion of patients who have a partial or complete response to therapy. |
Neoadjuvant therapies | Treatments administered before the main therapy, to help reduce the size of a tumor or kill cancer cells that have spread. |
Metronomic chemotherapy | A treatment in which low doses of anti-cancer drugs are given on a continuous or frequent, regular schedule (such as daily or weekly), usually over a long time. Metronomic chemotherapy causes less severe side effects than standard chemotherapy. |
Event-free survival (EFS) | The time after treatment for cancer when a patient remains free of certain complications or events that the treatment was intended to prevent. It is a term that denotes the possibility of having a particular group of defined events (could be a fracture, some lab test abnormality, a particular kind of progression such as brain metastasis, etc.) after a treatment that is designed to delay or prevent that group of events. |
Combined positive score (CPS) | Corresponds to the total number of tumor cells and immune cells (including lymphocytes and macrophages) stained with PD-L1 divided by the number of all viable tumor cells, then multiplied by 100. |
Complete response (CR) | The disappearance of all signs of cancer in response to treatment. |
Adjuvant therapies | Treatments administered after the primary therapy to try to kill the remaining cancer cells. |
References
- Robert, C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat. Commun. 2020, 11, 3801. [Google Scholar] [CrossRef] [PubMed]
- Jenkins, R.W.; Barbie, D.A.; Flaherty, K.T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 2018, 118, 9–16. [Google Scholar] [CrossRef] [PubMed]
- Pol, J.; Vacchelli, E.; Aranda, F.; Castoldi, F.; Eggermont, A.; Cremer, I.; Sautes-Fridman, C.; Fucikova, J.; Galon, J.; Spisek, R.; et al. Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology 2015, 4, e1008866. [Google Scholar] [CrossRef] [PubMed]
- Gandhi, L.; Rodriguez-Abreu, D.; Gadgeel, S.; Esteban, E.; Felip, E.; De Angelis, F.; Domine, M.; Clingan, P.; Hochmair, M.J.; Powell, S.F.; et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 2078–2092. [Google Scholar] [CrossRef]
- West, H.; McCleod, M.; Hussein, M.; Morabito, A.; Rittmeyer, A.; Conter, H.J.; Kopp, H.G.; Daniel, D.; McCune, S.; Mekhail, T.; et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019, 20, 924–937. [Google Scholar] [CrossRef]
- Zhu, S.; Zhang, T.; Zheng, L.; Liu, H.; Song, W.; Liu, D.; Li, Z.; Pan, C.X. Combination strategies to maximize the benefits of cancer immunotherapy. J. Hematol. Oncol. 2021, 14, 156. [Google Scholar] [CrossRef]
- Liu, P.; Chen, J.; Zhao, L.; Hollebecque, A.; Kepp, O.; Zitvogel, L.; Kroemer, G. PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer. Oncoimmunology 2022, 11, 2093518. [Google Scholar] [CrossRef]
- Kroemer, G.; Galassi, C.; Zitvogel, L.; Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 2022, 23, 487–500. [Google Scholar] [CrossRef]
- Zitvogel, L.; Pitt, J.M.; Daillere, R.; Smyth, M.J.; Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer 2016, 16, 759–773. [Google Scholar] [CrossRef]
- Ma, Y.; Adjemian, S.; Mattarollo, S.R.; Yamazaki, T.; Aymeric, L.; Yang, H.; Portela Catani, J.P.; Hannani, D.; Duret, H.; Steegh, K.; et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 2013, 38, 729–741. [Google Scholar] [CrossRef]
- Limagne, E.; Thibaudin, M.; Nuttin, L.; Spill, A.; Derangere, V.; Fumet, J.D.; Amellal, N.; Peranzoni, E.; Cattan, V.; Ghiringhelli, F. Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 Blockade in Colorectal Cancer by Inducing Immunogenic Cell Death and Depleting Macrophages. Cancer Immunol. Res. 2019, 7, 1958–1969. [Google Scholar] [CrossRef]
- Li, Y.; Zhang, H.; Li, Q.; Zou, P.; Huang, X.; Wu, C.; Tan, L. CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett. 2020, 495, 12–21. [Google Scholar] [CrossRef]
- Fukushima, H.; Yoshida, S.; Kijima, T.; Nakamura, Y.; Fukuda, S.; Uehara, S.; Yasuda, Y.; Tanaka, H.; Yokoyama, M.; Matsuoka, Y.; et al. Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti-PD-1 Treatment Efficacy in Urothelial Carcinoma. Int. J. Mol. Sci. 2021, 22, 535. [Google Scholar] [CrossRef]
- Shan, C.K.; Du, Y.B.; Zhai, X.T.; Wang, Y.X.; Li, Y.; Gong, J.H.; Ge, Z.J.; Liu, X.J.; Zhen, Y.S. Pingyangmycin enhances the antitumor efficacy of anti-PD-1 therapy associated with tumor-infiltrating CD8(+) T cell augmentation. Cancer Chemother. Pharmacol. 2021, 87, 425–436. [Google Scholar] [CrossRef]
- Yamazaki, T.; Buque, A.; Ames, T.D.; Galluzzi, L. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. Oncoimmunology 2020, 9, 1721810. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Shitara, K.; Moehler, M.; Garrido, M.; Salman, P.; Shen, L.; Wyrwicz, L.; Yamaguchi, K.; Skoczylas, T.; Campos Bragagnoli, A.; et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 2021, 398, 27–40. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Kawazoe, A.; Yanez, P.; Li, N.; Lonardi, S.; Kolesnik, O.; Barajas, O.; Bai, Y.; Shen, L.; Tang, Y.; et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 2021, 600, 727–730. [Google Scholar] [CrossRef]
- Voorwerk, L.; Slagter, M.; Horlings, H.M.; Sikorska, K.; van de Vijver, K.K.; de Maaker, M.; Nederlof, I.; Kluin, R.J.C.; Warren, S.; Ong, S.; et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: The TONIC trial. Nat. Med. 2019, 25, 920–928. [Google Scholar] [CrossRef]
- Peng, J.; Hamanishi, J.; Matsumura, N.; Abiko, K.; Murat, K.; Baba, T.; Yamaguchi, K.; Horikawa, N.; Hosoe, Y.; Murphy, S.K.; et al. Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-kappaB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. Cancer Res. 2015, 75, 5034–5045. [Google Scholar] [CrossRef]
- Demaria, S.; Volm, M.D.; Shapiro, R.L.; Yee, H.T.; Oratz, R.; Formenti, S.C.; Muggia, F.; Symmans, W.F. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin. Cancer Res. 2001, 7, 3025–3030. [Google Scholar]
- Muliaditan, T.; Opzoomer, J.W.; Caron, J.; Okesola, M.; Kosti, P.; Lall, S.; Van Hemelrijck, M.; Dazzi, F.; Tutt, A.; Grigoriadis, A.; et al. Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer. Clin. Cancer Res. 2018, 24, 1617–1628. [Google Scholar] [CrossRef] [PubMed]
- Hong, M.; Puaux, A.L.; Huang, C.; Loumagne, L.; Tow, C.; Mackay, C.; Kato, M.; Prevost-Blondel, A.; Avril, M.F.; Nardin, A.; et al. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 2011, 71, 6997–7009. [Google Scholar] [CrossRef] [PubMed]
- Kaneno, R.; Shurin, G.V.; Tourkova, I.L.; Shurin, M.R. Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J. Transl. Med. 2009, 7, 58. [Google Scholar] [CrossRef] [PubMed]
- Sistigu, A.; Yamazaki, T.; Vacchelli, E.; Chaba, K.; Enot, D.P.; Adam, J.; Vitale, I.; Goubar, A.; Baracco, E.E.; Remedios, C.; et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 2014, 20, 1301–1309. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.M.; Fowler, D.W.; Smith, P.; Dalgleish, A.G. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br. J. Cancer 2010, 102, 115–123. [Google Scholar] [CrossRef]
- Lacour, S.; Hammann, A.; Wotawa, A.; Corcos, L.; Solary, E.; Dimanche-Boitrel, M.T. Anticancer agents sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated caspase-8 activation and apoptosis. Cancer Res. 2001, 61, 1645–1651. [Google Scholar]
- Ramakrishnan, R.; Assudani, D.; Nagaraj, S.; Hunter, T.; Cho, H.I.; Antonia, S.; Altiok, S.; Celis, E.; Gabrilovich, D.I. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Investig. 2010, 120, 1111–1124. [Google Scholar] [CrossRef]
- Scurr, M.; Pembroke, T.; Bloom, A.; Roberts, D.; Thomson, A.; Smart, K.; Bridgeman, H.; Adams, R.; Brewster, A.; Jones, R.; et al. Low-Dose Cyclophosphamide Induces Antitumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer. Clin. Cancer Res. 2017, 23, 6771–6780. [Google Scholar] [CrossRef]
- Dimeloe, S.; Frick, C.; Fischer, M.; Gubser, P.M.; Razik, L.; Bantug, G.R.; Ravon, M.; Langenkamp, A.; Hess, C. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 2014, 44, 3614–3620. [Google Scholar] [CrossRef]
- Eriksson, E.; Wenthe, J.; Irenaeus, S.; Loskog, A.; Ullenhag, G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J. Transl. Med. 2016, 14, 282. [Google Scholar] [CrossRef]
- Alizadeh, D.; Trad, M.; Hanke, N.T.; Larmonier, C.B.; Janikashvili, N.; Bonnotte, B.; Katsanis, E.; Larmonier, N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014, 74, 104–118. [Google Scholar] [CrossRef]
- Kanterman, J.; Sade-Feldman, M.; Biton, M.; Ish-Shalom, E.; Lasry, A.; Goldshtein, A.; Hubert, A.; Baniyash, M. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res. 2014, 74, 6022–6035. [Google Scholar] [CrossRef]
- Huang, X.; Cui, S.; Shu, Y. Cisplatin selectively downregulated the frequency and immunoinhibitory function of myeloid-derived suppressor cells in a murine B16 melanoma model. Immunol. Res. 2016, 64, 160–170. [Google Scholar] [CrossRef]
- Sevko, A.; Michels, T.; Vrohlings, M.; Umansky, L.; Beckhove, P.; Kato, M.; Shurin, G.V.; Shurin, M.R.; Umansky, V. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J. Immunol. 2013, 190, 2464–2471. [Google Scholar] [CrossRef]
- Kwong, T.T.; Wong, C.H.; Zhou, J.Y.; Cheng, A.S.L.; Sung, J.J.Y.; Chan, A.W.H.; Chan, S.L. Chemotherapy-induced recruitment of myeloid-derived suppressor cells abrogates efficacy of immune checkpoint blockade. JHEP Rep. 2021, 3, 100224. [Google Scholar] [CrossRef]
- Ding, Z.C.; Munn, D.H.; Zhou, G. Chemotherapy-induced myeloid suppressor cells and antitumor immunity: The Janus face of chemotherapy in immunomodulation. Oncoimmunology 2014, 3, e954471. [Google Scholar] [CrossRef]
- Ding, Z.C.; Lu, X.; Yu, M.; Lemos, H.; Huang, L.; Chandler, P.; Liu, K.; Walters, M.; Krasinski, A.; Mack, M.; et al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res. 2014, 74, 3441–3453. [Google Scholar] [CrossRef]
- Wesolowski, R.; Duggan, M.C.; Stiff, A.; Markowitz, J.; Trikha, P.; Levine, K.M.; Schoenfield, L.; Abdel-Rasoul, M.; Layman, R.; Ramaswamy, B.; et al. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol. Immunother. 2017, 66, 1437–1447. [Google Scholar] [CrossRef]
- Lopez-Soto, A.; Gonzalez, S.; Smyth, M.J.; Galluzzi, L. Control of Metastasis by NK Cells. Cancer Cell 2017, 32, 135–154. [Google Scholar] [CrossRef]
- Gasser, S.; Orsulic, S.; Brown, E.J.; Raulet, D.H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005, 436, 1186–1190. [Google Scholar] [CrossRef]
- Acebes-Huerta, A.; Lorenzo-Herrero, S.; Folgueras, A.R.; Huergo-Zapico, L.; Lopez-Larrea, C.; Lopez-Soto, A.; Gonzalez, S. Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors. Oncoimmunology 2016, 5, e1074378. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Wang, D.; Li, Z.; Jiao, D.; Jin, L.; Cong, J.; Zheng, X.; Xu, L. Low-Dose Gemcitabine Treatment Enhances Immunogenicity and Natural Killer Cell-Driven Tumor Immunity in Lung Cancer. Front. Immunol. 2020, 11, 331. [Google Scholar] [CrossRef] [PubMed]
- Ghiringhelli, F.; Menard, C.; Puig, P.E.; Ladoire, S.; Roux, S.; Martin, F.; Solary, E.; Le Cesne, A.; Zitvogel, L.; Chauffert, B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 2007, 56, 641–648. [Google Scholar] [CrossRef] [PubMed]
- Pesce, S.; Greppi, M.; Tabellini, G.; Rampinelli, F.; Parolini, S.; Olive, D.; Moretta, L.; Moretta, A.; Marcenaro, E. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J. Allergy Clin. Immunol. 2017, 139, 335–346.e3. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Cheng, Y.; Xu, Y.; Wang, Z.; Du, X.; Li, C.; Peng, J.; Gao, L.; Liang, X.; Ma, C. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene 2017, 36, 6143–6153. [Google Scholar] [CrossRef]
- Hsu, J.; Hodgins, J.J.; Marathe, M.; Nicolai, C.J.; Bourgeois-Daigneault, M.C.; Trevino, T.N.; Azimi, C.S.; Scheer, A.K.; Randolph, H.E.; Thompson, T.W.; et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Investig. 2018, 128, 4654–4668. [Google Scholar] [CrossRef]
- Ansell, S.M.; Lesokhin, A.M.; Borrello, I.; Halwani, A.; Scott, E.C.; Gutierrez, M.; Schuster, S.J.; Millenson, M.M.; Cattry, D.; Freeman, G.J.; et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med. 2015, 372, 311–319. [Google Scholar] [CrossRef]
- Beldi-Ferchiou, A.; Lambert, M.; Dogniaux, S.; Vely, F.; Vivier, E.; Olive, D.; Dupuy, S.; Levasseur, F.; Zucman, D.; Lebbe, C.; et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 2016, 7, 72961–72977. [Google Scholar] [CrossRef]
- Dong, W.; Wu, X.; Ma, S.; Wang, Y.; Nalin, A.P.; Zhu, Z.; Zhang, J.; Benson, D.M.; He, K.; Caligiuri, M.A.; et al. The Mechanism of Anti-PD-L1 Antibody Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector. Cancer Discov. 2019, 9, 1422–1437. [Google Scholar] [CrossRef]
- Pasquier, E.; Kavallaris, M.; Andre, N. Metronomic chemotherapy: New rationale for new directions. Nat. Rev. Clin. Oncol. 2010, 7, 455–465. [Google Scholar] [CrossRef]
- Quartino, A.L.; Friberg, L.E.; Karlsson, M.O. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Investig. New Drugs 2012, 30, 833–845. [Google Scholar] [CrossRef]
- Tanaka, H.; Matsushima, H.; Mizumoto, N.; Takashima, A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 2009, 69, 6978–6986. [Google Scholar] [CrossRef]
- Karachi, A.; Yang, C.; Dastmalchi, F.; Sayour, E.J.; Huang, J.; Azari, H.; Long, Y.; Flores, C.; Mitchell, D.A.; Rahman, M. Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition. Neuro Oncol. 2019, 21, 730–741. [Google Scholar] [CrossRef]
- Wu, J.; Jordan, M.; Waxman, D.J. Metronomic cyclophosphamide activation of anti-tumor immunity: Tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. BMC Cancer 2016, 16, 623. [Google Scholar] [CrossRef]
- Tran, L.; Allen, C.T.; Xiao, R.; Moore, E.; Davis, R.; Park, S.J.; Spielbauer, K.; Van Waes, C.; Schmitt, N.C. Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma. Cancer Immunol. Res. 2017, 5, 1141–1151. [Google Scholar] [CrossRef]
- Chen, Q.; Xia, R.; Zheng, W.; Zhang, L.; Li, P.; Sun, X.; Shi, J. Metronomic paclitaxel improves the efficacy of PD-1 monoclonal antibodies in breast cancer by transforming the tumor immune microenvironment. Am. J. Transl. Res. 2020, 12, 519–530. [Google Scholar]
- Skavatsou, E.; Semitekolou, M.; Morianos, I.; Karampelas, T.; Lougiakis, N.; Xanthou, G.; Tamvakopoulos, C. Immunotherapy Combined with Metronomic Dosing: An Effective Approach for the Treatment of NSCLC. Cancers 2021, 13, 1901. [Google Scholar] [CrossRef]
- Maharjan, R.; Choi, J.U.; Kweon, S.; Pangeni, R.; Lee, N.K.; Park, S.J.; Chang, K.Y.; Park, J.W.; Byun, Y. A novel oral metronomic chemotherapy provokes tumor specific immunity resulting in colon cancer eradication in combination with anti-PD-1 therapy. Biomaterials 2022, 281, 121334. [Google Scholar] [CrossRef]
- Petrizzo, A.; Mauriello, A.; Luciano, A.; Rea, D.; Barbieri, A.; Arra, C.; Maiolino, P.; Tornesello, M.; Gigantino, V.; Botti, G.; et al. Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting. Oncotarget 2018, 9, 3576–3589. [Google Scholar] [CrossRef]
- Katsumata, N.; Yasuda, M.; Takahashi, F.; Isonishi, S.; Jobo, T.; Aoki, D.; Tsuda, H.; Sugiyama, T.; Kodama, S.; Kimura, E.; et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: A phase 3, open-label, randomised controlled trial. Lancet 2009, 374, 1331–1338. [Google Scholar] [CrossRef]
- Topalian, S.L.; Taube, J.M.; Pardoll, D.M. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020, 367, eaax0182. [Google Scholar] [CrossRef] [PubMed]
- Paz-Ares, L.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.J.; Ozguroglu, M.; Ji, J.H.; et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet 2019, 394, 1929–1939. [Google Scholar] [CrossRef] [PubMed]
- Dafni, U.; Tsourti, Z.; Vervita, K.; Peters, S. Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. Lung Cancer 2019, 134, 127–140. [Google Scholar] [CrossRef] [PubMed]
- Kwon, M.; Jung, H.; Nam, G.H.; Kim, I.S. The right Timing, right combination, right sequence, and right delivery for Cancer immunotherapy. J. Control. Release 2021, 331, 321–334. [Google Scholar] [CrossRef] [PubMed]
- Reck, M.; Bondarenko, I.; Luft, A.; Serwatowski, P.; Barlesi, F.; Chacko, R.; Sebastian, M.; Lu, H.; Cuillerot, J.M.; Lynch, T.J. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase 2 trial. Ann. Oncol. 2013, 24, 75–83. [Google Scholar] [CrossRef]
- Yan, Y.; Cao, S.; Liu, X.; Harrington, S.M.; Bindeman, W.E.; Adjei, A.A.; Jang, J.S.; Jen, J.; Li, Y.; Chanana, P.; et al. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight 2018, 3, e97828. [Google Scholar] [CrossRef]
- Galluzzi, L.; Humeau, J.; Buque, A.; Zitvogel, L.; Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 2020, 17, 725–741. [Google Scholar] [CrossRef]
- Paz-Ares, L.; Luft, A.; Vicente, D.; Tafreshi, A.; Gumus, M.; Mazieres, J.; Hermes, B.; Cay Senler, F.; Csoszi, T.; Fulop, A.; et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2040–2051. [Google Scholar] [CrossRef]
- Socinski, M.A.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodriguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N. Engl. J. Med. 2018, 378, 2288–2301. [Google Scholar] [CrossRef]
- Paz-Ares, L.; Ciuleanu, T.E.; Cobo, M.; Schenker, M.; Zurawski, B.; Menezes, J.; Richardet, E.; Bennouna, J.; Felip, E.; Juan-Vidal, O.; et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 198–211. [Google Scholar] [CrossRef]
- Forde, P.M.; Spicer, J.; Lu, S.; Provencio, M.; Mitsudomi, T.; Awad, M.M.; Felip, E.; Broderick, S.R.; Brahmer, J.R.; Swanson, S.J.; et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N. Engl. J. Med. 2022, 386, 1973–1985. [Google Scholar] [CrossRef]
- Blank, C.U.; Rozeman, E.A.; Fanchi, L.F.; Sikorska, K.; van de Wiel, B.; Kvistborg, P.; Krijgsman, O.; van den Braber, M.; Philips, D.; Broeks, A.; et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 2018, 24, 1655–1661. [Google Scholar] [CrossRef]
- Horn, L.; Mansfield, A.S.; Szczesna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2220–2229. [Google Scholar] [CrossRef]
- Cortes, J.; Cescon, D.W.; Rugo, H.S.; Nowecki, Z.; Im, S.A.; Yusof, M.M.; Gallardo, C.; Lipatov, O.; Barrios, C.H.; Holgado, E.; et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020, 396, 1817–1828. [Google Scholar] [CrossRef]
- Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kummel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; Harbeck, N.; et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2020, 382, 810–821. [Google Scholar] [CrossRef]
- Schmid, P.; Adams, S.; Rugo, H.S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Dieras, V.; Hegg, R.; Im, S.A.; Shaw Wright, G.; et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2018, 379, 2108–2121. [Google Scholar] [CrossRef]
- Burtness, B.; Harrington, K.J.; Greil, R.; Soulieres, D.; Tahara, M.; de Castro, G., Jr.; Psyrri, A.; Baste, N.; Neupane, P.; Bratland, A.; et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 2019, 394, 1915–1928. [Google Scholar] [CrossRef]
- Sun, J.M.; Shen, L.; Shah, M.A.; Enzinger, P.; Adenis, A.; Doi, T.; Kojima, T.; Metges, J.P.; Li, Z.; Kim, S.B.; et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 2021, 398, 759–771. [Google Scholar] [CrossRef]
- Doki, Y.; Ajani, J.A.; Kato, K.; Xu, J.; Wyrwicz, L.; Motoyama, S.; Ogata, T.; Kawakami, H.; Hsu, C.H.; Adenis, A.; et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N. Engl. J. Med. 2022, 386, 449–462. [Google Scholar] [CrossRef]
- Powles, T.; Park, S.H.; Voog, E.; Caserta, C.; Valderrama, B.P.; Gurney, H.; Kalofonos, H.; Radulovic, S.; Demey, W.; Ullen, A.; et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 2020, 383, 1218–1230. [Google Scholar] [CrossRef]
- Oh, D.Y.; Lee, K.H.; Lee, D.W.; Yoon, J.; Kim, T.Y.; Bang, J.H.; Nam, A.R.; Oh, K.S.; Kim, J.M.; Lee, Y.; et al. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: An open-label, single-centre, phase 2 study. Lancet Gastroenterol. Hepatol. 2022, 7, 522–532. [Google Scholar] [CrossRef] [PubMed]
- Colombo, N.; Dubot, C.; Lorusso, D.; Caceres, M.V.; Hasegawa, K.; Shapira-Frommer, R.; Tewari, K.S.; Salman, P.; Hoyos Usta, E.; Yanez, E.; et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N. Engl. J. Med. 2021, 385, 1856–1867. [Google Scholar] [CrossRef] [PubMed]
- Johnson, M.L.; Cho, B.C.; Luft, A.; Alatorre-Alexander, J.; Geater, S.L.; Laktionov, K.; Kim, S.W.; Ursol, G.; Hussein, M.; Lim, F.L.; et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J. Clin. Oncol. 2023, 41, 1213–1227. [Google Scholar] [CrossRef] [PubMed]
- O’Brien, M.; Paz-Ares, L.; Marreaud, S.; Dafni, U.; Oselin, K.; Havel, L.; Esteban, E.; Isla, D.; Martinez-Marti, A.; Faehling, M.; et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022, 23, 1274–1286. [Google Scholar] [CrossRef] [PubMed]
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Sordo-Bahamonde, C.; Lorenzo-Herrero, S.; Gonzalez-Rodriguez, A.P.; Martínez-Pérez, A.; Rodrigo, J.P.; García-Pedrero, J.M.; Gonzalez, S. Chemo-Immunotherapy: A New Trend in Cancer Treatment. Cancers 2023, 15, 2912. https://doi.org/10.3390/cancers15112912
Sordo-Bahamonde C, Lorenzo-Herrero S, Gonzalez-Rodriguez AP, Martínez-Pérez A, Rodrigo JP, García-Pedrero JM, Gonzalez S. Chemo-Immunotherapy: A New Trend in Cancer Treatment. Cancers. 2023; 15(11):2912. https://doi.org/10.3390/cancers15112912
Chicago/Turabian StyleSordo-Bahamonde, Christian, Seila Lorenzo-Herrero, Ana P. Gonzalez-Rodriguez, Alejandra Martínez-Pérez, Juan P. Rodrigo, Juana M. García-Pedrero, and Segundo Gonzalez. 2023. "Chemo-Immunotherapy: A New Trend in Cancer Treatment" Cancers 15, no. 11: 2912. https://doi.org/10.3390/cancers15112912